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Abstract
MicroRNAs (miRNAs) have proven to be critical regulators of both the HIV-1 virus itself and of the immune response that it instigates. Additionally, circulating miRNAs appear to be promising biomarkers for the disease conditions that HIV-1 infected anti-retroviral therapy (ART) treated individuals are at risk for. This thesis attempts to explore the immunomodulatory role of miRNAs during HIV-1 infection and investigates their potential as biomarkers in HIV-1 infected ART treated individuals.
A set of 21 miRNAs were measured in the serum of a group of HIV-1 infected, ART treated individuals that were divided into cases, individuals who died whilst on therapy, and their matched controls. While there were no clear associations between the miRNAs and mortality (all-cause, cardiovascular and malignancy), some of the miRNAs of the miRNAs correlated with established biomarkers of mortality, IL-6, D-dimer and CD4+ T cell count.
Additionally, two miRNAs, miR-122 and miR-200a, were significantly associated with liver disease in the same patient set. The expression of both miRNAs was increased in the serum and the purified small circulating vesicles of individuals who died from liver related causes. These data suggest that miR-122 and miR-200a may be effective biomarkers for liver disease in ART treated individuals.
MiR-9 expression is significantly down-regulated in the CD4+ T cells of individuals with chronic progressive HIV-1 infection compared to long term non-progressors and healthy controls. This miRNA can be encoded from 3 different locations in the genome. However, it appears that pri-miR-9-1 is responsible for the overwhelming majority of expression of miR-9 in CD4+ T cells. Differences in pri-miR-9-1 also mimic the changes of mature miR-9 in an in vitro model of memory CD4+ T cells. Additionally, evidence suggests that methylation of the DNA region upstream of pri-miR-9-1 may be contributing to the differential expression of mature miR-9 in naïve and memory CD4+ T cells.
Expression of miR-378 is clearly reduced in the monocytes of individuals with chronic progressive HIV-1 infection compared to LTNPs and healthy controls. Evidence from an in vitro model of monocyte infection suggests that this reduction is caused by IFN-α. IFN-α is a critical regulator of the anti-viral innate immune response and its regulation of miR-378 suggests that this miRNA may have an important role to play in the anti-viral innate immune response.
In conclusion miRNAs are important, but subtle, contributors to HIV-1 related pathogenesis and may be effective biomarkers for adverse outcome in ART treated individuals.